Heterogeneity in regional and cellular responses to neurotoxic chemicals has long been recognized, however, the cellular basis for selective vulnerability is poorly understood. Certain nuclei in the phylogenetically older regions of the brain are exquisitely sensitive to several chemically unrelated neurotoxicants. Many of these chemicals perturb mitochondrial glutathione (GSH) homeostasis and energy metabolism. It is hypothesized that regional differences in astrocytic mitochondrial (mt) glutathione homeostasis render specific populations of astrocytes in the brainstem vulnerable to chemically induced energy deprivation syndromes. Chemicals that are widely believed to act on energy metabolism, nevertheless, do not affect all mitochondria equally. Neurotoxicants such as 1,3- dinitrobenzene (DNB) which produce damage similar to those observed in "Acute Energy Deprivation Syndromes" (AEDS) or idiopathic mitochondrial diseases also affect glutathione status. While considerable emphasis has been placed on altered energy metabolism in these syndromes, regional, cellular and subcellular glutathione homeostasis have been largely ignored. The relationships and interdependencies between glutathione and energy metabolism are complex and require further investigation with respect to selective neurotoxicant vulnerability. The central hypothesis of this proposal will be tested by addressing the following specific questions: 1) What are the differences in regional, cellular and subcellular glutathione status and homeostasis? 2) Does modulation of cellular antioxidant status alter regional mitochondrial susceptibility to neurotoxicant-induced oxidative stress? 3) Do astrocytic mitochondria selectively metabolize DNB and render themselves vulnerable to glutathione depletion via opening of the mitochondrial permeability transition (MPT) pore? In vitro and in vivo models that produce distinct astrocytic lesions will aid in determination of the role of mtGSH in the etiology of AEDS. The proposed studies will provide information on mechanisms of oxidative stress which contribute to the loss of specific brain cell populations following exposure to neurotoxic chemicals. This work will lead to better understanding of selective vulnerability and its role in neurotoxic syndromes.